Mannose triflate

Cheng-Lee et al. (2005) demonstrated the multistep synthesis of a radiolabeled imaging probe in a PDMS microreactor, consisting of a complex array of reaction channels, with typical dimensions of 200 pm (wide) 45 pm (deep). Employing a sequence of five steps, comprising of (1) [18F] fluoride concentration (500 /iCi), (2) solvent exchange from H20 to MeCN, (3) [18F]fluoride substitution of the D-mannose triflate 252 (324 ng), to afford the labeled probe 253 (100 °C for 30 s and 120 °C for 50 s), (4) solvent exchange from MeCN to H20, and finally, (5) acid hydrolysis of 254 at 60 °C, the authors demonstrated the synthesis of 2-[18F]-FDG 254 (Scheme 72). 

The synthesis of2-deoxy-2- F-fluoro-D-glucose (2-[ F]FDG) [153-155] is another example where the application of microwaves can reduce the synthesis time and increase the radiochemical yields. An initial optimization of the standard nucleophilic fluorination with mannose triflate under microwave conditions cut short... 

Schematic representation of a chemical reaction circuit used in the production of 2-deoxy-2-fluoro-D-glucose (FDG). Five sequential processes are shown (() concentration of dilute fluoride ion with the use of a miniaturized anion exchange column located in a rectangle-shaped fluoride concentration loop, (ii) solvent exchange from water to dry MeCN, (Hi) fluorination of the D-mannose triflate precursor 1, (tv) solvent exchange back to water.

PET imaging is performed with positron emitting radiopharmaceuticals. After collision of the emitted positrons with electrons, pairs of gamma-rays are formed that are detected by the PET camera. The most important PET tracer is F-Fludeoxyglucose ( F-FDG) with a physical half-life of 110 min. F-FDG is nowadays synthesised by nucleophilic substitution of the precursor mannose triflate using fully automated synthesis procedures and cyclotron-produced F-fluoride ions. After purification the resulting... 

In the first instance, research focused on investigating if the fluorination step could be conducted within microreactors. Steel [47] used a microfluidic chip [channel dimensions, 300 pm (wide) x 50 pm (deep)], where a solution of mannose triflate (44) in anhydrous acetonitrile is reacted with a premade complex from [ F] KF, Kryptofix 2.2.2 and K2CO3 in acetonitrile. They reported a 40% conversion for the radiolabeling reaction [(44) to (45)] when a residence time of 2 min was used. 

Gillies and coworkers [48,49] subsequently used a polycarbonate microreactor, in which a chamber was designed to effect very rapid turbulent mixing. The microreactor was used to conduct the fluorination of mannose triflate (44), followed by acid hydrolysis of the intermediate (45) to synthesize [ F]fluorodeoxyglucose ([ F] FDG) (46) (Scheme 6.15), whereby 50% overall incorporation of the radiolabel was achieved with a residence time of just 4 s. However, the polymeric material did limit what solvents could be used within the system. 

Undoubtedly, the most sophisticated synthesis of [ F]FDG was reported by Gheng-Lee et al. [51]. They used a PDMS microreactor consisting of a complex array of channels typically 200 pm wide and 45 pm deep. They employed a sequence of five steps, comprising (i) fluoride concentration (500 pCi), (ii) solvent exchange from water to acetonitrile, (iii) nucleophilic substitution of the mannose triflate (44)... 

Scheme 4.35 Glycosyl triflate formation in the mannose series.

Hodosi and Kovac reported the highly efficient P-mannosylation, which makes use of mannose-derived 1,2-O-stannylene acetal 15 in combination with an aglycon-derived triflate (Scheme 7.13).58 A remarkable feature of this method is its extreme simplicity. Even totally unprotected mannose can be used as precursor of 15. Undoubtedly, this method can be seen as one of the most facile methods for the stereoselective synthesis of P-mannosides. 

Scheme 7.13 (3-Mannosylation using mannose-derived 1,2-O-stannylene acetal in combination with an aglycon-derived triflate.

The influence of the 4,6-O-benzylidene acetal in p-mannosylations was believed to be due to its torsional disarming effect. In an earlier work, Bert Fraser-Reid and coworkers found that a 4,6-O-benzylidene acetal locks the pyranose ring in a stable chair conformation [41], Therefore, it disfavors the formation of an intermediate oxocarbenium ion, which requires rehybridization and flattening of the sugar ring, usually leading to ahalf-chair conformation. This torsional effect, combined with the strong endo-mom nc effect in mannose, favors the a-triflate intermediate. 

A most promising development is the observation that dibutylstannylene acetals of L-rhamnose and D-mannose derivatives having 0-1 and 0-2 unprotected react with primary and secondary triflates of sugars under mild conditions to give in good yields cis-(l— 2)-linked disaccharides with inversion in the glycosyl acceptor (see Fig. 57).230 As noted in Table X, L-rhamnose derivatives give better yields than shown for the mannose derivatives in Fig. 57. 

Srivastava and Schuerch [112] and Dessings et al. [113]. reported on the potential utility of 1,2-O-stannylene acetals in /3-wianno-glycoside synthesis. Recently, Hodosi and Kovac established a highly efficient /3-mannosylation process involving alkylation of a 1,2-O-stannylene acetal with the triflate derived from an aglycon [ 114] (O Scheme 39). A remarkable feature of this method is its extreme simplicity. Even free mannose can be used as a precursor of... 

Mannose is converted to methyl /3-D-mannoside with methyl sulfate in an alkaline medium. This coupling is the opposite of all those we have considered thus far the bridge oxygen comes from the glycosyl donor. This type of reaction has been used in the preparation of disaccharides, with the use of sugar triflate as electrophile (Schmidt 1986). 

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